The present invention relates to transgenic mice which express CREB. These transgenic mice provide a genetic model of dilated cardiomyopathy.
Congestive heart failure (CHF) is a leading cause of cardiovascular morbidity and mortality affecting more than 4 million Americans and representing the most common reason for hospitalization of patients over the age of 65 (1, 2). Idiopathic dilated cardiomyopathy (IDC), a primary myocardial disease of unknown etiology characterized by ventricular dilatation and depressed myocardial contractility is an important cause of CHF with an estimated prevalence of 36 cases/100,000 (3-7). Relatively little is known about the molecular mechanisms underlying the pathogenesis of IDC. Progress in this area has been limited by the lack of animal models that closely resemble the anatomical and clinical features of the human disease.
Several previously described genetically modified mice have been reported to develop cardiomyopathies. These include mice expressing mutant forms of {character pullout}-myosin heavy chain ({character pullout}-MHC), mice engineered to ectopically express the myf5 bHLH transcription factor in the heart, and mice containing targeted mutations of the muscle LIM protein (MLP) (49-51). However, the phenotypes of each of these mice differs significantly from that of the transgenic mice described herein. Unlike the transgenic mice of the present invention, which display progressive cardiac dilatation without hypertrophy, the {character pullout}-MHC and myf5 mice develop a hypertrophic cardiomyopathy with myocyte disarray and interstitial fibrosis (50, 51). Consistent with these histological findings, the {character pullout}-MHC mice display normal end systolic LV pressures and dP/dtmax but abnormal LV relaxation. These findings are highly reminiscent of the phenotype of patients with hypertrophic as opposed to dilated cardiomyopathy. The phenotype of the transgenic mice of the present invention also differed significantly from that of the recently described muscle LIM protein (MLP)-deficient mice which display soft, markedly hypertrophic hearts with grossly abnormal sarcomere structure within the first several weeks after birth (49). Unlike the transgenic mice of the present invention, 50-70% of the MLP-deficient mice die before 10 days of age.